The main goal of this application is to define the biological responses through which carboxyl ester lipase (CEL) genetic mutations increase risk for chronic pancreatitis (CP) in humans. Almost 50% of idiopathic CP in adults and 75% of children with CP have genetic susceptibility driven by mutations in genes encoding pancreatic digestive enzymes. Most of these patients have acute recurrent pancreatitis (ARP) before developing CP. If the episodes of ARP can be stopped, it is likely we can stop the progression to CP. Knowledge about how genetic mutations increase CP risk is critical for developing novel therapies to prevent CP. We will model the process using genetic mutations of CEL, some of which cause autosomal-dominant CP. Our previous work showed that this mutation causes the protein to misfold and accumulate in the cell. The accumulated protein triggers endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). If these responses do not restore protein balance in the ER, inflammatory and cell death pathways are activated. Our overriding hypothesis is that proteins encoded by genetic risk variants of CEL cause pancreatitis by disrupting protein balance in the ER. To address our hypothesis and advance our understanding of the pathophysiology of CP, we will systematically phenotype novel, humanized mouse models of CEL genetic risk variants that cause chronic pancreatitis. We will methodically investigate the cellular responses triggered by expression of pathogenic human genetic variants of CEL utilizing cell culture and mouse models. Finally, we will determine whether chemical chaperones or enhancers of degradative pathways alter the accumulation of mutant CEL. Completion of these studies will establish mutation-induced misfolding of digestive enzymes as a relevant disease mechanism in the pathogenesis of CP and will identify potential therapeutic targets to stop ARP and prevent CP.